PPEF2 encodes a calcium-dependent serine/threonine phosphatase with EF-hand motifs that functions as a negative regulator of stress-responsive signaling pathways. The protein binds calmodulin in a calcium-dependent manner through its N-terminal IQ motif, enabling dual regulation of its catalytic activity 1. In the retina, PPEF2 is abundantly expressed in photoreceptors and localizes to rod inner segments, where it may participate in visual signaling, though knockout studies indicate it is not essential for normal rhodopsin dephosphorylation or light responses in mice 2. PPEF2 acts as a potent antagonist of apoptosis signal regulating kinase-1 (ASK1), suppressing oxidative stress-induced activation of p38 and JNK MAP kinases and preventing caspase-3 cleavage 3. Recently, PPEF2 was identified as an opponent of PINK1-mediated mitophagy in Parkinson's disease through dephosphorylation of ubiquitin at serine 65, thereby suppressing mitochondrial quality control 4. In schizophrenia, rare missense variants in PPEF2 influence metabotropic glutamate receptor (mGluR5) levels 5, while in high myopia, PPEF2 variants reduce protein expression and impair cell migration and proliferation while promoting apoptosis in retinal tissues 6. These findings suggest PPEF2 serves as a critical hub in neuroprotection, synaptic signaling, and cellular quality control.